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Genetics of Bone Density

A new study linked 32 novel genetic regions to bone mineral density. The findings may help researchers understand why some people are more susceptible to bone fractures. The research also points to potential drug targets for preventing or treating osteoporosis.

Bones are made of a mineral and protein scaffold filled with bone cells. Bone is continually broken down and replaced. When the rate of bone loss outpaces the rate of replacement, bones weaken, eventually leading to osteoporosis and increased risk of fracture. More than 40 million people nationwide either have osteoporosis or are at increased risk for broken bones because of low bone mineral density (osteopenia).

Past studies suggest that genetic differences may account for more than half the variance in bone mineral density between people. Previous genome-wide association studies identified 24 genetic regions that influence bone mineral density. However, these genetic variants explained a small fraction of the variation in bone density, and none were shown to influence the risk of fracture in a definitive way.

A worldwide consortium with multiple research groups set out to do the largest search to date for variants related to bone mineral density. The effort was funded by many sources, including the European Commission and several NIH components, such as the National Institute on Aging (NIA) and National Institute for Arthritis, Musculoskeletal and Skin Diseases (NIAMS). The extensive research team—led by a group at Erasmus Medical Center in Rotterdam, the Netherlands—also included scientists at NIA. The study appeared online in Nature Genetics on April 15, 2012.

The researchers first combined data from 17 different studies involving more than 80,000 people across North America, Europe, East Asia and Australia. They looked across the genome for genetic variants associated with bone mineral density of the femoral neck and lumbar spine. The researchers found 96 independent variations from 87 genomic regions.

The scientists next tested these associations in over 50,000 more people from 34 other studies. They confirmed the association with bone mineral density in 56 regions, 32 of which hadn't been previously been tied to bone density.

The team also examined whether the 96 variants were associated with bone fractures. They analyzed data from 50 studies with fracture information. Combined, the studies involved over 31,000 people with fractures and over 102,000 controls. Fourteen of the regions, the researchers found, were also associated with bone fracture risk.

These findings reinforce the relationship between genetic factors and the risk of osteoporosis and bone fracture. However, the researchers found that the ability to use these factors to predict risk was modest relative to clinical risk factors such as age and weight.

“In reality, there may be 500 or more gene variants regulating osteoporosis,” says
Dr. John Ioannidis of the Stanford University School of Medicine, one of the
senior authors. “Each variant conveys a small quantum of risk or benefit.
We can't predict exactly who will or won't get a fracture.”

“The ultimate goal of genetic studies like this is to develop personal, gene-based treatments for osteoporosis as well as to better identify those at high risk for the disease,” says another of the senior authors, Dr. Douglas P. Kiel of Harvard Medical School. “The findings could lead to new therapies to prevent or treat osteoporosis.”